tbuckley/cabot-search huggingface dataset:
Abstract 14196: Methamphetamine Use is Associated With Increased In-Hospital Mortality After Aortic Dissection: The National Inpatient Sample Perspective
Authors: Philippe F Nyembo, Abdulrahman Gamam
Journal: Circulation (2022)

Introduction: Aortic dissection is a rare complication associated with methamphetamine abuse. Mortality in aortic dissection is high, however outcomes in methamphetamine associated aortic dissection have not been investigated. In this study, we describe the impact of methamphetamine use on in-hospital mortality in patient who presented with an acute aortic dissection using a large inpatient database. Methods: We queried the 2017 National Inpatient Sample database to identify all admissions age 18 years or older with a discharge diagnosis of aortic dissection. We accounted for survey design and built a multivariable logistic regression model to evaluate the impact of methamphetamine use on in-hospital mortality after an acute aortic dissection, while controlling for patient demographics, hospital characteristics and multiple co-morbid conditions. Results: A total of 30,060 cases of acute aortic dissection were identified, of which 395 had a history of methamphetamine use disorder. Patients with aortic dissection and history of methamphetamine use disorder were younger, male with higher incidence of co-morbid smoking and history hypertension compared to those without history of methamphetamine use disorder (Table 1). We found that in-hospital mortality for aortic dissection was significantly higher among methamphetamine users despite controlling for multiple co-morbid conditions and patient demographics, OR 3.52 (95% CI 1.73 - 7.13); p - value 0.001. Conclusions: To our knowledge, this is the first population study to demonstrate that patients with a history of methamphetamine use disorder are at increased risk of death in the hospital after acute aortic dissection. Factors contributing to these findings necessitates further prospective investigations to prevent morbidity. Special attention should be paid to young patients presenting with aortic dissection and methamphetamine use disorder should be suspected.
Abstract 13054: The Novel Galnac-Conjugated Rnai Trigger Downregulates Apoc3 and Triglyceride Levels in Humanized Liver Mouse Model
Authors: Vivek Shah, Michael Molyneaux, Dmitry Samarsky
Journal: Circulation (2022)

Background: Hypertriglyceridemia is a critical risk factor for coronary artery disease. Apolipoprotein C-III (APOC3), produced by liver hepatocytes, regulates triglyceride (TG) levels. We studied effect of novel GalNAc-conjugated APOC3 targeting RNAi trigger (STP125G) on APOC3 and TG levels in humanized liver mouse model. Methods: In dose response study, female uPA-SCID mice (n=4 mice/group), group 1 received PBS control, group 2 received 10mg/kg and group 3 received 30mg/kg STP125G, subcutaneously on day 0. Liver biopsies, plasma and serum samples were collected at week 2. In duration response study, male uPA-SCID mice (n=4 mice/group/timepoint), group 1 received PBS control and group 2 received 10mg/kg STP125G, subcutaneously on day 0. Liver biopsies, plasma and serum samples were collected for each group at weeks 2, 4, 8 and 12. Human APOC3 mRNA (qPCR) and protein (ELISA) levels were measured in liver biopsies and plasma samples, respectively. TGs and total cholesterol (TC) levels were measured in serum samples. Results: In dose response study, animals reported significant suppression of mRNA and reduction of plasma protein levels in 10mg/kg (88% and 91%, respectively) and 30mg/kg (92% and 98%, respectively) dose groups as compared to control group ( p &lt;0.001). Animals also reported significant reductions in TGs and TC levels at 10mg/kg (25% and 33%, respectively) and 30mg/kg (43% and 44%, respectively) dose groups as compared to control group ( p &lt;0.05). In duration response study, treated animals reported significant suppression of mRNA levels at week 2 (83%), week 4 (85%) and week 8 (48%) as compared to control group ( p &lt;0.0001). Treated animals reported significant reduction in plasma protein levels at week 2 (82%; p &lt;0.0001), week 4 (89%; p &lt;0.0001) and week 8 (70%; p =0.0005) as compared to control group. At week 4, treated animals reported significant reduction in TGs (53%; p=0.0079) and TC (36%; p=0.0072). Conclusions: The studies demonstrated that a single administration of STP125G, in a humanized liver mouse model, results in significant suppression of human APOC3 mRNA and plasma protein levels that lasts for up to 8 weeks. It also suggests treatment with STP125G results in lowering of triglycerides and total cholesterol in the treated animals.
Abstract 13871: Tamponade Physiology: To Tap or Not to Tap?
Authors: Hussein Al Sudani, Kevin B Lo, rafal ali, Nora Hajnoczky, Bruce Casipit, Joseph Alexander Paguio, Ammaar Wattoo, Isaac Ogunmola, Christine Adekayode, Hamza Akhtar, Ruchika Bhargav, Gregg S Pressman
Journal: Circulation (2022)

Introduction: Cardiac tamponade is often evaluated through echocardiography. However, not all patients with tamponade physiology develop clinical tamponade. Thus, we evaluated various echocardiographic and clinical factors as predictors of the need for intervention. Methods: A total of 264 patients with tamponade physiology were extracted from the echocardiographic database. We compared clinical and demographic factors among those who underwent intervention vs. conservative care. Factors with p value of &lt;0.2 were included in a multivariable logistic regression model. Results: 76% of these patients had moderate to large pericardial effusions, and their mean MAP was 92 mmHg. Half of these patients (n=134) had either pericardiocentesis or a pericardial window. Only 7 patients (3%) required a repeat pericardiocentesis.Intervention patients had more positive echocardiographic parameters (2 (1-3) vs 1.5 (1-2) p&lt;0.001) and moderate to large pericardial effusions (90% vs 62% p&lt;0.001). On multivariable logistic regression, uremic or CKD-related effusion was independently associated with less interventions OR 0.22; 95% CI (0.07-0.67) p=0.007 while systolic RA collapse, diastolic RV collapse, IVC plethora and tricuspid inflow variation were all independently associated with higher odds of pericardial intervention AUC of overall model 0.81, 95 percent CI [0.76-0.86]. Conclusions: In this sample of patients with tamponade physiology on echocardiography, a model using a combination of echo and demographic parameters demonstrated good but not perfect discrimination in predicting the need for intervention. Clinical judgment remains important.
Abstract 14114: Sex Differences in the Etiology and Burden of Heart Failure Across the Sociodemographic Index: Analysis of 204 Countries and Territories, 1990-2019
Authors: Sunny Wei, J. Jaime Miranda, Mamas Mamas, Liesl Zuhlke, Evan Kontopantelis, Lehana Thabane, Harriette G Van Spall
Journal: Circulation (2022)

Background: Heart failure (HF) is a global epidemic. Objectives: We assessed sex differences in HF across country income. Methods: Using Global Burden of Disease (GBD) data, we assessed sex differences in HF prevalence, etiology, morbidity, and temporal trends between 1990-2019 across 204 countries and territories and disaggregated results by country income (SDI or gross national income). Results: In 2019 there were 56.2 million (95% uncertainty interval [UI] 46.4-67.8 million) HF cases worldwide, with over half in females. HF morbidity was estimated at 5.1 million (95% UI 3.3-7.3 million) years lived with disability, distributed equally between the sexes. Overall, ischemic heart disease was the top cause of HF in males, and hypertensive heart disease the top cause in females. Between 1990-2019, there was an increase in total HF cases, but the age-standardized rate per 100,000 decreased by 7.1%, more so in males (9.1%) than females (5.8%). High-income regions experienced a 16.0% temporal decrease in age-standardized rates, from 877.5 to 736.8 per 100,000, while low-income regions experienced a 3.9% increase, from 612.1 to 636.0 per 100,000. Trend directionality was largely consistent in both sexes. Asia, sub-Saharan Africa, and Middle East experienced a temporal increase in age-standardized HF rates in both sexes, related to increasing ischemic heart disease. Globally, there was an increase in age-standardized HF rates due to calcific aortic valve disease and hypertensive heart disease, and a decrease due to ischemic heart disease, although regional and sex differences were noted. Conclusions: Age-standardized HF rates are increasing in the Middle East and low-SDI regions of the world, with sex differences in etiology and trends that offer targets for intervention.
Abstract 13518: Augmenting SOD2 Levels in <i>Apoe</i> <sup>-/-</sup> Mice With Peptide-mRNA Nanoparticles Preserves Atherosclerotic Plaque Stability in Advanced Atherosclerosis
Authors: Aleksandr E Vendrov, Andrey Lozhkin, Hua Pan, Samuel A Wickline, Marschall Runge, Nageswara R Madamanchi
Journal: Circulation (2022)

Erosion or rupture of the advanced atherosclerotic plaque is the leading cause of atherosclerosis complications such as acute coronary syndrome and stroke. Atherosclerotic plaques in aging hypercholesterolemic mice have decreased SOD2 levels and increased mitochondrial oxidative stress, which leads to cell apoptosis, necrotic core expansion, and fibrous cap thinning and rupture. We hypothesized that increasing SOD2 expression in advanced atherosclerotic plaque cells in mice using mRNA polyplex would protect mitochondria from oxidative damage and preserve plaque stability. Macrophages isolated from Sod2 +/- mice treated with amphipathic cationic peptide p5RHH: Sod2 mRNA polyplexes had markedly increased levels of Sod2 mRNA and mitochondrial SOD2 (p&lt;0.01), higher SOD activity, which resulted in lower levels of mitochondrial and cellular reactive oxygen species (ROS) and improved mitochondrial function. RNA-Seq analysis showed that macrophages treated with Sod2 nanoplexes had broadly decreased inflammatory cytokines and immune activation pathways. In Apoe -/- mice, atherosclerotic lesions with vulnerable plaque features were induced in the carotid artery by placing a perivascular collar over the carotid artery and 4-months Western diet. Mice were treated for 4 weeks with saline or with 0.5 mg/kg p5RHH: Sod2 mRNA polyplexes which selectively accumulated in atherosclerotic lesion macrophages. The carotid plaques of the mice treated with Sod2 mRNA differed significantly from the plaques of the control Apoe -/- mice by higher SOD2 expression, lower mitochondrial ROS and oxidative DNA damage, and reduced expression of CCL2, IL1, IL6, MMP 2 and 9 (p&lt;0.01). Sod2 polyplexes-treated mouse plaques exhibited 25% fewer inflammatory macrophages (p&lt;0.01) and 98% more smooth muscle cells (p&lt;0.001) with a reduced lipid core, preserved fibromuscular cap, and decreased plaque vulnerability index (p&lt;0.05). The results suggest that selective overexpression of Sod2 in plaque macrophages using nanoplexes reduces mitochondrial stress and preserves plaque stability without adverse effects. Using nanoparticle-based mRNA therapeutics to modulate plaque morphology has great potential in the prevention and treatment of atherosclerosis complications.
Abstract 13123: Sex-Specific Associations Between Hypertension in the Early Forties and Arterial Stiffness 27 Years Later: The Hordaland Health Study
Authors: Ester Kringeland, Helga Midtbo, Eva Gerdts
Journal: Circulation (2022)

Background: Hypertension is associated with arterial stiffening. Less is known about sex-specific associations of hypertension in the early forties with increased arterial stiffness later in life. Methods: BP was measured in 1121 women and 932 men at mean age 42 years (baseline). Participants were grouped into normotension (BP&lt;130/80 mmHg), stage 1 hypertension (BP 130-139/80-89 mmHg) and stage 2 hypertension (BP≥140/90 mmHg). Arterial stiffness was measured by pulse wave velocity (PWV) after 27 years follow-up. Increased arterial stiffness was defined as PWV&gt;10m/s in both sexes. Associations between baseline BP categories and increased arterial stiffness were tested in logistic regression analyses and presented as odds ratios (OR) and 95% confidence intervals (CI). Results: At baseline, a larger proportion of men than women had stage 1 and stage 2 hypertension (330 men (35%) and 266 women (24%) with stage 1 and 241 men (26%) and 105 women (9%) with stage 2 hypertension, p&lt;0.001 for sex difference). At follow-up, 289 men (31%) and 197 women (18%) had increased arterial stiffness (p&lt;0.01). In univariable analysis in women, stage 1 (OR 2.44, 95 % CI 1.72-3.47) and stage 2 hypertension (OR 3.34, 95% CI 2.10-5.31) were associated with increased arterial stiffness. After adjustments for baseline body mass index, smoking, heart rate, serum cholesterol and education, stage 1 (OR 2.19, 95% CI 1.52-3.15) and stage 2 hypertension (OR 2.74, 95% CI 1.67-4.48) remained associated with increased arterial stiffness in women. In univariable analyses in men, stage 1 (OR 1.55, 95% CI 1.11-2.16) and stage 2 hypertension (OR 1.88, 95% CI 1.32-2.68) were associated with increased arterial stiffness. After similar multivariable adjustments, these associations became non-significant in men (OR 1.34, 95% CI 0.95-1.89 for stage 1 and OR 1.40, 95% CI 0.95-2.06 for stage 2 hypertension, respectively). This sex difference was confirmed by a significant test for interaction (p=0.03). Conclusion: In the Hordaland Health Study, having stage 1 and stage 2 hypertension in the early forties predicted increased arterial stiffness in women, but not in men.
Abstract 13316: Multi-Ancestry Genome-Wide Association Analysis in 1.9 Million Individuals Identifies 49 New Genetic Loci for Heart Failure and Related Subtypes
Authors: Albert Henry, Tom Lumbers
Journal: Circulation (2022)

Introduction: Characterization of the genetic etiology of heart failure (HF) provides an opportunitiy to advance understanding of causal human biology and to develop genomic tools for prediction and patient stratification. We conducted a multi-ancestry genome-wide association meta-analysis of HF and related subtypes in 1.9 million individuals. Methods: We investigated 10,199,961 common genetic variants for association with all-cause HF (145,795 cases); non-ischemic HF, defined as the absence of antecedent myocardial infarction and abnormal loading conditions (44,030 cases); and non-ischemic HF stratified by left ventricular ejection fraction (LVEF) (5,407 cases of LVEF &lt;50% and 3,846 cases of LVEF 50%). By synthesizing evidence from functionally-informed fine-mapping, in silico gene prioritization, and multi-tissue transcriptome-wide association analysis, we prioritized likely causal variants, effector genes, and tissues for HF. We tested for enrichment of genes linked to Mendelian disorders within genomic loci for HF and assessed the genetic correlation of HF-related traits and their causal inter-relationships using Mendelian randomization. Results: We identified 56 independent genomic loci, including 39 novel, associated with all-cause HF; and additional 10 novel independent genomic loci among non-ischemic HF subtypes at P &lt; 5 x 10-8. Genomic loci for HF were enriched for genes associated with Mendelian disorders of cardiomyopathy (Padjusted = 0.01) and arrhythmia (Padjusted = 0.0006). In 30 / 56 loci for all-cause HF, functionally-informed fine-mapping identified 5 or fewer likely causal variants. Genetically predicted expression levels of 266 genes across 49 human tissues were associated with HF at a false discovery rate &lt;1%, 95 (36%) of which were also identified in heart tissue-specific analysis. Genetic correlation and causal associations were detected between upstream risk factors and traits of cardiac structure and function, yielding new insights into HF endophenotype relationships. Conclusion: These findings extend our understanding of the etiology of the HF syndrome and provide new opportunities to inform the development of new therapeutic strategies.
Abstract 14077: Human Placental CDX2 Cells Are Multipotent and Differentiate Robustly to Cardiomyocytes
Authors: Sangeetha Vadakke-Madathil, Bingyan Wang, saeed seyedmohammad, Koen Raedschelders, Erdenechimeg Baljinnyam, Micayla Oniskey, Fumiko Dekio, Rachel Brody, Shari Gelber, Samuele Marro, Jennifer E Van Eyk, Rhoda Sperling, Hina W Chaudhry
Journal: Circulation (2022)

Regenerative biology hinges on exploration of evolutionarily preserved healing mechanisms to maintain and restore homeostasis. CDX2 is one such conserved factor that regulates trophoblast stem cell differentiation in the placenta. We previously demonstrated that murine placental Cdx2 lineage cells are multipotent and restored cardiac function even in male mice after myocardial infarction. We have now isolated CDX2 cells from over 35 patients’ placentas and studied their properties. Using huCDX2 promoter-driven mCherry lentivirus, CDX2 cells were isolated and multi-omics analyses were carried out versus H9ES cells. In vitro cardiac and vascular differentiation was examined. CDX2 cells expressed HLAG (50.5%±5) and cytokeratin7 (95%±5) supporting a trophoblast progenitor identity. Bulk RNA-seq showed 1065 upregulated genes. Differentially expressed genes like NKX2.5, GATA4 , and TBX5 attribute a cardiac committed progenitor feature to CDX2 cells. CDX2 cells downregulated pluripotency markers negating concerns of any undesirable proliferation. Whole-cell proteome of CDX2 cells revealed 252 unique proteins of which 73 were upregulated involving development and immune modulation including FGF, EFGR, and the Map kinase/ERK pathway crucial for cardiac development, in addition to unique cell surface proteins, which can be utilized in place of lentivirus for live-cell selection. When plated on neonatal murine cardiomyocyte feeders, CDX2 cells robustly differentiated into beating cardiomyocytes expressing cTnT and alpha-actinin. Using an alternate feeder-free method, we observed 80-90% cTnT expression in differentiated CDX2 cardiomyocytes. Additionally, CDX2 cells gave rise to endothelial lineage cells expressing vWF. CDX2 cells further formed tube-like structures on matrigel-based endothelial assays and demonstrated uptake of acetylated LDL suggesting functional endothelial generation. We further demonstrated that CDX2 cells can be passaged and significantly expanded ex vivo (50,000 to 1million cells), while retaining cardiovascular potential. These results bring us closer to translation as placenta-derived CDX2 cells may form the basis for a novel clinical approach to cardiovascular regeneration.
Abstract 13011: A Rare Case of Spontaneous Coronary Artery Dissection
Authors: Dmitri Zbarsky, evan sternberg, Bobby Diniotis, Zeina Ibrahim, Daniela Kovacs
Journal: Circulation (2022)

Introduction: Spontaneous coronary artery dissection (SCAD) is a rare condition; an intimal tear or bleeding of vasa vasorum leads to the creation of a false lumen filled with intramural hematoma. The hematoma causes coronary stenosis, leading to subsequent myocardial ischemia. SCAD is the cause of Acute Coronary Syndrome (ACS) in 0.1 to 4% of cases. Men account for less than 10% of cases, with a mean age of 48.6. Case Study: A 19-year-old male with prior medical history of morbid obesity and marijuana use was transferred from another hospital to our service after presenting with non-ST elevation MI. He was admitted following 30 minutes of a throbbing/pressure-like sensation in his throat, one episode of vomiting, and paresthesia in his left arm that spontaneously resolved. Initial EKG showed sinus rhythm with early repolarization changes. His troponin rose from 0.2 to 18 ng/mL. Upon admission, his high sensitivity troponin peaked at 15,000 pg/mL. Repeat EKG showed dynamic changes with T wave inversions in the inferolateral leads. The patient underwent an angiogram showing a diffuse, mid-LAD 40% de novo spontaneous dissection and a diffuse, distal-LAD 20% de novo spontaneous dissection with TIMI grade 3 and 2 flow, respectively. A repeat angiogram two days later showed improved coronary artery flow and deemed a low-risk lesion with stable patient hemodynamics; no intervention followed. The patient was treated conservatively with DAPT and discharged home with an outpatient Cardiology follow-up. A plan to have further imaging in 4 weeks to assess hematoma resolution was made. Conclusions: This case demonstrates an atypical presentation of SCAD in a very low-risk patient, given his sex, age, and clinical presentation of nonspecific chest pain. This case highlights the importance of high clinical suspicion for SCAD regardless of ACS risk profile in a patient presenting with chest pain.
Abstract 13676: Sublingual Nitroglycerin Lowers Aortic Augmentation Pressure at Rest and During Exercise in Patients With HFpEF
Authors: Denis J Wakeham, Seamus B Hughes, Joetsaroop S Bagga, Bryce N Balmain, Andrew R Tomlinson, Tony G Babb, James P Macnamara, Christopher M Hearon, Benjamin D Levine, Satyam Sarma
Journal: Circulation (2022)

Infusion or inhalation of organic nitrates lower ascending aortic pressures, and reduce mid-late systolic afterload via a reduction in augmentation pressure (aAP, the difference between the first [aP1] and second [aP2] peaks of the aortic pressure waveform) at rest and during exercise in patients with heart failure and preserved ejection fraction (HFpEF). Sublingual nitroglycerin (NTG) is more accessible for patients as compared to the infusion or inhalation of nitrates. It is unknown whether NTG spray (400μg) elicits these same effects as organic nitrates on aortic hemodynamics at rest and during exercise. Therefore, in 15 patients with HFpEF (age, 71 ± 6 years; 10 women; BMI 39.2 ± 6.2 kg/m 2 ), as part of our ongoing clinical trial, we measured beat-by-beat radial artery blood pressure and estimated aortic pressure in real-time via a generalized inverse transfer function (SphygmoCor). Data were collected in the seated upright position at rest and throughout six-minutes of cycling at 20 Watts during either a placebo or NTG condition (randomized order). Stroke volume (SV) was calculated from cardiac output (Qc, acetylene rebreathe) and heart rate (ECG). NTG lowered stroke volume at rest, but not during exercise (Table); however, SV responses to exercise were similar (Placebo: Δ22 ± 19 vs NTG: Δ25 ± 18 ml, P = 0.1991). Aortic diastolic pressure was not different at rest with NTG compared to placebo (Table). aP1 and aP2 were lower at rest with NTG, with greater reductions in aP2 (Table). NTG lowered aAP during rest (Placebo: 11 ± 11 vs NTG: 0 ± 14 mmHg, P = 0.0002) and exercise (Placebo: 12 ± 11 vs NTG: 4 ± 12 mmHg, P &lt; 0.0001). These results suggest patients with HFpEF do not augment SV responses to exercise despite a lower aAP contribution to (mid-late) systolic afterload with NTG. The inability to take advantage of a lower aAP during exercise may reflect impairments in contractile function and end-systolic reserve.